Kanaan Lab

 

About the Kanaan Lab

Insert summary of Kanaan Lab and key research areas.

Lab Personnel

Nicholas M. Kanaan, PhD, Primary Investigator

Benjamin Combs

Matt Benskey

Tessa Grabinski

Mohammed Alhadidy

Ahmed Atwa

Olivia Leighton

Rebecca Mueller

 

Tau Toxicity (Tau-Mediated Axonal Degeneration)

Alzheimer's disease and other tauopathies are devastating aging-related neurodegenerative diseases. These diseases are characterized by the accumulation of abnormally modified tau proteins, which is closely linked to the observed cognitive deficits. Some of the earliest pathological changes, especially in AD, follow a "dying-back" pattern in which axons are the first to exhibit abnormal structural changes. A likely pathogenic factor contributing to axonal degeneration is the protein tau, as it is critical in maintaining axonal function. Indeed, studies using human tissue and animal model systems suggest that tau abnormalities and axonal degeneration are interconnected components of the early degenerative sequelae of AD.

Our lab studies how disease-related modifications of tau alter its structure in ways that lead to tau-mediated axonal dysfunction and degeneration.  We have primarily focused on pathways through which pathological tau conformations (---link to tau conformations project tab---) lead to the activation of phosphatases/kinases that impair axonal transport in neurons. Our lab uses a multifaceted approach to address study this issue ranging from molecular biology, protein biochemistry, cell culture models, in vivo models and human tissue samples.  

If successful, this project will identify a molecular mechanism for tau-induced axon dysfunction/degeneration that could be targeted for disease-modifying therapeutic interventions in AD patients, as well as those suffering from other tauopathies.

Tau Antibodies

Tau is a microtubule-associated protein that is known for its role in several neurodegenerative disease known as tauopathies. The protein was discovered in the 70’s and shortly after was recognized as the protein composing the hallmark tangle pathologies in Alzheimer’s disease (AD). Over the years, novel monoclonal tau antibodies have played an instrumental role in driving new discoveries and giving critical insights into tau biology and pathobiology, normal tau distribution within neurons and the importance of protein modifications under physiological and pathological conditions. Our lab continues to generate novel tau antibodies to advance our understanding of tau and to uncover mechanisms driving tau toxicity. For example, our lab has developed multiple antibodies against specific pathological conformations of tau that have helped uncover mechanisms whereby disease-related forms of tau lead to axonal toxicity (---link to axonal project---). Additionally, our antibody work has supported studies on tau oligomers and have helped establish that they can disrupt axonal function, synaptic activity, neurophysiology and ultimately cause toxicity in neurons. These relatively unique reagents were instrumental in demonstrating that specific tau conformations are among the first changes that occur during the evolution of tau pathology in Alzheimer’s disease and other tauopathies. Thus, antibodies are more than simple reagents. They act as a link between in vitro and systems models and human disease. Our reagents drive not only our research program, but also many other national and international research groups.

The overall goal of this project is to leverage our past experience in making tau reagents to continue driving innovation, discovery, and novel therapeutics for tauopathies.

Tau SIMOA

Alzheimer’s disease (AD) and AD-related dementias have a severe impact on those affected, the healthcare system and the US economy.

The development of ultrasensitive assays such as the single molecule array (SIMOA) platform has facilitated a significant biomarker opportunity that may transform the current landscape and have a large impact on our ability to manage these diseases. The SIMOA technology allows the detection of very low levels of tau, a microtubule-associated protein that composes the hallmark pathologies of tauopathies, in plasma and other biofluids. Continued pursuit of CSF biomarkers is critical, but plasma provides an important opportunity to potentially obtain critical biomarker information through routes that are relatively non-invasive, inexpensive and easy to collect serially in large volumes. Currently, there is a critical need for developing novel tau-based assays. Our lab’s overall goal is to use our large resource of established, well-characterized monoclonal tau antibodies and newly created and characterized tau monoclonal antibodies (---link to tau antibody project tab---) to develop a series of novel SIMOA assays for tau in plasma and CSF. We are developing tau assays that detect total tau by targeting specific epitopes throughout the protein. Additionally, we will develop novel tau assays that detect specific pathogenic forms of tau in plasma and CSF.

Developing such assays is critical to advance the field toward obtaining assays with high specificity, sensitivity, reproducibility and predictability for identifying tauopathies, such as AD and other ADRD tauopathies.